HUT76645A - N-substituted naphthofused lactams, pharmaceutical compositions containing them and their use - Google Patents

Description

The present invention relates to novel N-substituted naphtho-linked lactams and their salts, processes for their preparation and pharmaceutical compositions containing them. The present invention also encompasses the use of the compounds as medicaments and their use in the treatment of diseases resulting from growth hormone deficiency.

Growth hormone is a hormone that stimulates the growth of any tissue that can grow. In addition, growth hormone is known to affect many metabolic processes, such as stimulating protein synthesis and releasing free fatty acids and resulting in a shift from carbohydrate to fatty acid metabolism in energy metabolism. As a result, growth hormone deficiency can be a source of many serious diseases such as dwarfism.

Growth hormone is produced in the pituitary gland. Its release is strictly regulated by many hormonal and neurotransmitter transducers, either directly or indirectly. Growth hormone production can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases, the hormones are released by the hypothalamus, but their action is primarily mediated by specific receptors in the pituitary gland. Other components that stimulate pituitary growth hormone production have also been described. For example, alginin, L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP, muscarinic receptor agonists and some synthetic hexapeptides, GHRP (= growth hormone releasing peptide) or by a direct effect on the pituitary or • ···· ·· · · · · · ·· • • • · · · · · · · · · · · · · · · · • · ^r By stimulating the release of GHRH and / or somatostatin produced by the 3 hypothalamus, they stimulate endogenous growth hormone release.

For diseases where it would be desirable to raise growth hormone levels, due to the nature of the growth hormone protein, parenteral administration is not feasible. In addition, other direct acting production enhancers such as GHRH, GHRP and PACAP are known to date and there are also long chain proteins which, by their nature, cannot be administered orally. However, many indirect active compounds can be administered orally, such as L-Dopa and muscarinic receptor antagonists, although the use of these compounds is hindered by the side effects they induce.

The present invention relates to compounds of a non-protein nature capable of stimulating endogenous growth hormone production. These novel compounds may be administered, inter alia, parenterally, or via the nasal mucosa or orally.

WO 92/16524, WO 94/07483, WO 94/07486, WO 94/05634, WO 95/09633, WO 95/12598, WO 95/03289 and WO 95/03290 U.S. Patent Nos. 5,310,737; 5,283,241; 5,284,841; 5,374,721; 5,273,046; and UK Patent No. 2,273,046, are incorporated as agents for enhancing human and animal growth hormone production. protected N-substituted benzo-linked lactams in which the N-substituent is a substituted phenyl or biphenyl group. Other N-substituted benzo-linked lactams in which the N-substituent comprises various heterocycles are disclosed in WO 94/07486, WO 94/08583

International Patent Application Publication No. i, and U.S. Patent No. 5,284,841. U.S. Patent No. 4,228,156 and International Patent Application WO 94/11012 disclose synthetic dipeptides, and International Patent Application WO 94/13696 disclose spiropiperidines linked to benzo-linked lactams as growth hormone release agents.

The compounds of the present invention differ from those described in the references cited above in that they are linked in a lactam naphthalene ring.

In addition to the references cited above, U.S. Patent Nos. 5,124,328 and 5,077,290 disclose N-substituted-2-heterocyclic morpholine derivatives as animal growth promoters. Further, U.S. Patent Nos. 5,030,640, 4,906,645 and 5,019,578 disclose aminoethanol derivatives as animal growth promoters.

The present invention relates to novel N-substituted naphtho-linked lactams of formula I wherein

R ¹ , R ² and R ³ are each independently hydrogen, halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylthio; n is 0 or 1; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and w is 0, 1, or 2; X is -O-,> S (O) _m , or> NR ⁴ where R ⁴ is hydrogen or C 1-6 alkyl; m is 0, 1 or 2;

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

A group is a or b, or c or d, each of which has one or two substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy. may be substituted by alkyl; and Y is = Ν-, Z is -O-, -S- or> NR ⁵ wherein R ⁵ is hydrogen or C 1-6 alkyl.

Group B is selected from the group consisting of e or f or g or h, each of which has one or two substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy. may be substituted by alkyl; and Y and Z have the same meanings as defined above;

M is -COOR ¹² , -CON R ¹² R ¹³ , -NHCONR ¹² R ¹³ or -SONR ¹² R ¹³ , wherein R ¹² and R ¹³ are each independently hydrogen, C 1-6 alkyl or C 4-8 cycloalkyl or M is a tetrazole, triazole, oxadiazole and thiadiazole isomer selected from one or two of the following substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylthio ;

D is a group of the formula wherein r and s are independently 0, 1, 2 or 3; Is ^R7 and ^R8 are independently hydrogen or C1-10 alkyl; or the groups R ⁷ and R ^{8 may} be linked to form an alkyl bridge, the bridge being 2 to 6 carbon atoms; or each of R ⁷ and R ⁸ may independently be linked to one or all of R ⁹ or R ¹⁰ to form an alkyl bridge (s) wherein the bridge consists of 2 to 5 carbon atoms; R ⁹ and R ¹⁰ are independently hydrogen, phenyl, substituted phenyl, branched or unbranched C 1 -C 10 alkyl, or branched or unbranched C 1 -C 10 hydroxyalkyl; or pharmaceutically acceptable salts thereof.

In each of the formulas herein, n, p, q, w, m, r and s are in each case an integer or zero.

The compound of formula (I) of the present invention can be prepared by the following process:

The procedure

The procedure is illustrated in Scheme 1. The compound of formula (II), R ^1, R ^2, R ^3, X, D group, and n and p are as defined above, with a compound of formula (III) is reacted: wherein wherein A, B groups, and w and q are as defined above and L is a suitable protecting group such as halogen, para-toluenesulfonate or mesylate. This alkylation reaction can be carried out in a solvent such as Ν, Ν-dimethylformamide or dimethylsulfoxide in the presence of a base such as sodium hydride up to the reflux temperature of the solvent, for example for 1 to 120 hours.

• · · · ·

Compounds of formula (II) may be prepared in a manner analogous to that described in WO 92/16524, and compounds of formula (III) may be synthesized by methods known to those skilled in the art. (See, for example, Comprehensive Heterocyclic Chemistry, vol. 5, & 6, Pergamon Press, 1984; Heterocyclic Compounds, vol. 7, Wiley, 1961.)

Under certain circumstances, it may be necessary to provide intermediates used in the above processes, such as compounds of Formulas II and III, with suitable protecting groups. When a primary or secondary amino group is present, as in the compounds of formula II, this amino group may be protected, for example, by a methoxysulfonyl or benzyloxycarbonyl group. For example, in the compounds of formula (III) where acidic groups are present, these groups may be esterified. In addition, in the compounds of formula III where tetrazole is present, it is possible, for example, to tritylate it. The introduction and removal of such protecting groups are, for example, described in Protective Groups in Organic Synthesis, W. Greene and P. G. M. Wuts 2nd ed. (John Wiley & Sons Inc.).

The compounds of formula (I) may exist in the form of geometric and optical isomers, of course, all such isomers and mixtures thereof are included within the scope of the invention. The isomers may be isolated by standard techniques such as chromatography or fractional crystallization of their corresponding salts.

Preferred compounds of the formula I are, for example, a

3-Amino-3-methyl-N- (4-oxo-5- (2 '- (tetrazol-5-yl) biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) butyramide,

3-amino-3-methyl-N- (4-oxo-5- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) thien-3-yl) benzyl ) -2,3,4,5-Tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) -butyramide, 3- (2R) -hydroxypropylamino) -3-methyl-N- (5- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) thien-3-yl) benzyl) -4-oxo-2,3,4,5- tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) butyramide,

-aminocyclopropanecarboxylic acid (4-oxo-5- [2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl-methyl) -2,3,4,5- tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) -amide,

3-Amino-3-methyl-N- (5-benzyl-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) -butyramide.

The compounds of the present invention may exist in the form of any pharmaceutically acceptable acid addition salts or esters.

Pharmaceutically acceptable acid addition salts or esters of the compounds of formula I include derivatives of inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, succinic acid, tartaric acid, toluenesulfonic acid, sulfamic acid and fumaric acid.

Surprisingly, it has been found that the compounds of formula (I) have remarkable pharmacological properties, and the compounds of formula (I) have been shown to have the ability to stimulate endogenous growth hormone production. Accordingly, these compounds may be used in the treatment of conditions in need of increased growth hormone production or secretion, such as growth hormone deficiency in humans or in cases where elevated plasma levels of growth hormone are desirable, such as in the elderly or livestock.

• · 'I

Growth hormone-producing compounds of formula (I) are in vitro devices for use in assays of growth hormone production control systems.

The compounds of formula (I) may also be used as a means of determining the ability of the pituitary to produce growth hormone. For example, serum samples taken before and after administration of the compounds to humans can be assayed for growth hormone levels. Comparison of growth hormone levels in each serum sample may provide an opportunity to determine the growth hormone production capacity of the patients' pituitary gland.

The compounds of formula I are useful in increasing the size and growth rate of commercially important animals and increasing their milk production.

Accordingly, the present invention also provides pharmaceutical compositions containing, as an active ingredient, at least one of the compounds of formula I as carriers or solvents. Optionally, the pharmaceutical compositions may contain, in addition to the compounds of formula (I), one or more other non-active compounds, such as antibiotics or other pharmaceutically active substances.

The growth hormone production stimulating compounds of formula (I) are further used in combination with other secretagogues such as GHRP (2 or 6), GHRH growth hormones and analogues, or the IGF-1 and IGF- second

It is well known to those skilled in the art that the actual and potential use of human growth hormone varies and can vary widely. Therefore, the compounds of formula (I) may be administered for the purpose of stimulating pituitary growth hormone production and have the same effect as the growth hormone itself. The use of growth hormone can be summarized as follows: stimulating growth hormone production in old age; avoiding catabolic (breakdown) side effects of glucocorticoid (adrenal hormone); treatment of osteoporosis; stimulation of the immune system; treatment of retardation; accelerating wound healing; accelerating the onset of bone fracture; treating growth failure; treating kidney disease or insufficient kidney function due to growth failure; low physiological growth, including growth hormone deficiency in children and low levels associated with chronic disease; treating obesity and obesity-related growth retardation; treating growth retardation associated with Prader-Willi syndrome and Turner syndrome; shortening hospital treatment time and healing of burn victims; treatment of intrauterine growth retardation, bone malformation, dysplasia, hypercorticalism (increased function of the adrenal cortex) and Cushing's syndrome; treatment of periodically accelerated growth hormone release; adjusting growth hormone levels in stress patients; treatment of osteochondrodysplasia (bone and cartilage disorder), Noonan syndrome, schizophrenia, depression, Alzheimer's disease, wound healing in psychosocial cases; pulmonary function and respiratory dependence, treatment of protein dilution, mainly as a catabolic response after surgery, treatment of chronic diseases such as cancer or cachexia and protein loss due to AIDS; treatment of hyperinsulinemia (increased blood insulin profile), including nesidioblastosis; ovulation-inducing adjuvant treatment; stimulating the development of the baby's gland and preventing age-related decline in thymic function; treatment of immunosuppressed patients; improving muscle strength and agility, maintaining skin thickness, maintaining old-age metabolic balance, maintaining kidney homeostasis; stimulating the function of osteoblasts (bone-forming cells), bone remodeling and cartilage growth, stimulating the immune system of pets and treating disorders in aging domestic animals, accelerating the growth of livestock and increasing the growth of sheep wool.

PHARMACOLOGICAL TESTING METHODS

The activity and potency of growth hormone production in primary rat somatotrophs was measured in vitro. Primary rat somatotrophes were prepared essentially as described previously in the prior art (See, e.g., Chen et al., Endocrinology 1991, 129, 3337-3342 and Chen et al., 1989, 124, 2791-2798). Briefly, rats and the pituitary gland was rapidly removed. The pituitary gland was digested in equilibrium saline containing 0.2% collagenase and 0.2% hyaluronidase. Cells were resuspended in Dulbecco's modified medium containing 0.37% NaHCO ₃ , 10% horse serum, 2.5% fetal bovine serum, 1% non-elemental amino acids, 1% glutamine and 1% pen / strep, and the cell concentration was 1.5 x It was adjusted to 10 ⁵ cells / ml. The ···· ·· ·· * ·· • · · · · · · · · · · · • · · · · · · ·· ** * ¹ 12 suspensions in 24-well plates used in each well 1 ml and were allowed to stand for 2 to 3 days prior to hormone production experiments.

On the day of the experiments, cells were washed twice with pH 7.4 medium containing 25 mM HEPES above. Growth hormone secretion was induced by addition of a solution containing 25 mM HEPES and test compound. The mixtures were incubated for 15 minutes at 37 ° C. Following incubation, the amount of growth hormone secreted in the assay medium was determined by standard RIA assay.

The effects of the compounds of formula (I) on growth hormone production were investigated in vivo in pentobarbital anesthetized female rats, as previously described in the prior art. (See, e.g., Bercu et al., Endocrinology 1991, 129, 2592-2598.) Briefly, adult male Sprague-Dawley rats were anesthetized with 70 mg / kg of lung (ip = intrapulmonary ingested) pentobarbital. After the rats had completely fallen asleep, catheters were inserted into their trachea and catheters were inserted into the carotid artery (A. carotis) and the cervical vein (V. jugularis). Blood samples were taken 15 minutes after waking up at time 0. The pituitary secretion enhancer was administered intravenously and the arterial blood samples were placed on ice for 15 minutes and centrifuged for 2 minutes at 20,000 x g. Serum was filtered by decantation and GH levels were determined by standard RH assay.

For each of the indications listed above, the dosage employed will always depend on the compound of formula (I) employed, the mode of administration and the desired therapy. However, in order to know for the people and animals of endogenous growth hormone production increase effective dosage ·· · ·· "·· · · · · · · • • • ·· · · · · · ·· ·· · ¹ >

Generally, the amounts or dose levels are between 0.0001 and 100 mg / kg body weight per day. In oral dosage forms, the dosage of the compound of Formula I mixed with a carrier or diluent is generally about 0.0001 mg / kg to about 500 mg / kg, preferably about 0.001 mg / kg to about 100 mg / kg. kg.

The compounds of formula (I) of the present invention may also be administered in the form of pharmaceutically acceptable acid addition salts or, where appropriate, in the form of the corresponding alkali metal or alkaline earth metal or lower alkyl ammonium salts. These salt forms exhibit approximately the same activity as the free base form.

Pharmaceutical compositions containing the compounds of the present invention may be prepared by conventional methods and may be formulated in conventional forms, for example capsules, tablets, solutions or suspensions.

The pharmaceutical carriers used in the preparation may be conventional, solid or liquid. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

Similarly, solid and liquid carriers may be slow or delayed release agents known in the art, such as glyceryl monostearate or glyceryl distearate alone or in admixture with resin.

In the case of an oral solid dosage form, they may be tabletted, filled into a hard gelatin capsule in powder or pellet form, or in the form of lozenges or lozenges. The amount of solid carrier employed may vary widely but will generally be from about 25 mg to about 1 gram. When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injection such as an aqueous or non-aqueous liquid suspension or solution.

In general, the compounds of the present invention are divided into unit doses containing from 50 to 200 mg of the active ingredient, and are formulated in unit dosage form or in a pharmaceutically acceptable carrier or in admixture with one another.

Dosages of the compounds of the present invention are suitably in the range of 1 to 500 mg / day, for example, when administered to a patient, such as a human, at a dose of 100 mg per day.

Typical tablet formulations obtainable by conventional tabletting techniques are listed in Table 1 below:

·· ···· · «· · · · · · · · · · ·

Table 1

Mag: Active ingredient (in free form or in salt form) 100 mg Colloidal Silica (Areosir) 1.5 mg Cellulose, microcrystalline (Avicel * ') 70 mg Modified Cellulose Rubber (Ac-Di-Soi “) 7.5 mg Coating: HPMC approx 9 mg * Mywacett ^{J <)} 9-40 T approx 0.9 mg

* Acylated monoglyceride used as a plasticizer for film coating.

The pharmaceutical compositions of the present invention may be administered by any route that effectively delivers the active ingredient to the site where it may produce the desired or desired effect, and may be administered orally, dermally, nasally, lung or parenterally, i.e., the gastrointestinal tract. by-pass, of which oral administration is preferred.

EXPORTING EXAMPLES

The following exemplary embodiments are provided to further illustrate the process for the preparation of the compounds of formula (I) and compositions containing them without limiting the scope of the invention.

The molecular structure of the compounds obtained was determined either by elemental analysis or by NMR. NMR shifts (d) are given in parts per million (ppm). The O.p. the abbreviation refers to the melting point and is given in ° C. Column chromatography was performed by W.C. Still et al., J. Org. Chem. 1978, 43, 2923-2925, was performed using Merck Silica gel 60 (Item No. 9385). The compounds used as starting materials in the processes are either known compounds or can be readily prepared by methods known per se.

abbreviations:

TLC: Thin layer chromatography TFA: trifluoroacetic acid DMSO: dimethylsulfoxide DMF: Ν, Ν-dimethylformamide EDAC 1-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride HOAt: hydroxy-azabenzotriazole HOBt: hydroxybenzotriazole THF: tetrahydrofuran AIBN: azo-iso-butyronitrile NBS: N-bromosuccinimide

HPLC analysis:

Eljár 'mode of operation

RP-HPLC analysis was performed at 214 nm with a UV detector and a Vydac 218TP54 4.6 mm x 250 mm 5m C-18 silica gel column (The Separations Group, Hisperia) at 42 ° C, eluting at 1 ml / min. The column was equilibrated with 5% (v / v) CH ₃ CN in 0.1M (NH ₄ ) ₂ SO ₄ buffer, which was adjusted to pH 2.5 with 4M H ₂ SO ₄ . During equilibrium treatment, elution was performed with a CH ₃ CN gradient of 5 (v / v)% to 60 (v / v)% in the above buffer for 50 minutes.

Procedure 'B'

The same column was eluted according to Method Ά 'for 50 minutes at 0 (v / v)% CH ₃ CN / 0.1 (v / v)% TFA / CH ₃ CN / 0.1 containing up to 90 (v / v)% H ₂ O (v / v) using a% TFA / H ₂ O gradient.

Procedure C *

Elution on a 5 mm C-18 4 x 250 mm column with a gradient of 20 to 80 (v / v)% 0.1 (v / v)% TFA / acetonitrile and 0.1% TFA / water for more than 25 minutes and T = 35 ° C.

Example 1

3-Amino-3-methyl-N- (4-oxo-5- (2 '- (tetrazol-5-yl) biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro-1H -naphtho [2,1-b] azepin-3-yl] -butyramide trifluoroacetate

3,4-Dihydro-2H-phenanthren-1-one oxime

Sodium acetate trihydrate (7.07 g, 52 mmol) was dissolved in water (30 mL) and hydroxylamine hydrochloride (3.61 g, 52 mmol) was added. Ethanol (75 mL) and 3,4-dihydro-2H-phenanthren-1-one (5.0 g, 26 mmol) were added and the resulting suspension was heated under reflux for 2 hours. The reaction mixture was cooled in an ice bath and the precipitated solid was collected by filtration, washed with cold water and dried under vacuum to give 4.8 g of 3,4-dihydro-2H-phenanthren-1-one oxime.

174-175 ° C. ¹ H NMR (CDCl 3) δ 2.05 (ρ, 2Η, J = 8 Hz); 2.91 (t, 2Η, J = 8 Hz); 3.20 (t, 2H, J = 8Hz); 7.52 (m, 2H); 7.67 (d, 1H, J = 9Hz); 7.82 (d, 1H, J = 9Hz); 8.05 (t, 2H, J = 9Hz); 8.22 (brs, 1H).

A solution of 4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-blazepine] in methanesulfonic acid and 5.2 g (37 mmol) of phosphorus pentoxide was heated at 90 ° C for 3.5 hours. . The solution was cooled to 50 ° C and 3,4 grams (23 mmol) of 3,4-dihydro-2H-phenanthren-1-one oxime was added. The solution was heated at 60 ° C for 10 minutes and then at 80 ° C for 3.5 hours. The hot reaction mixture was added to a mixture of 300 grams of ice and 100 ml of water. The precipitated solid was collected by filtration, redissolved in dichloromethane (50 mL), dried over magnesium sulfate, and concentrated in vacuo to give a white product. The product was purified by column chromatography using 200 g of silica gel and heptane-ethyl acetate (1: 2 by volume). This gave 4.8 g of 4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine.

Mp: 186-187 ° C ¹ H NMR (CDCl 3) δ 2.16 (t, 2H, J = 8 Hz); 2.21-2.30 (m, 2H); 3.14 (t, 2H, J = 8Hz);

7.19 (d, 1H, J = 9Hz); 7.46 (t, 1H, J = 9Hz); 7.55 (t, 1H, J = 9 Hz); 7.80 (d, 1H,

J = 9 Hz); 7.90 (d, 1H, J = 9Hz); 8.13 (d, 1H, J = 9Hz); 9.71 (s, 1H). 3,3-Dichloro-4-oxo-2,3,4,5-tetrahydro-1 H-blazepin naftof2,1

A suspension of 4.8 g (23 mmol) of 4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine and 125 ml of toluene was added and 14.2 g (68 mmol) of phosphorus pentachloride were added. and the reaction mixture was maintained at 90 ° C for one hour. After cooling the mixture to room temperature, the solvent was concentrated in vacuo and the residue was suspended in 50 ml of glacial acetic acid. The slurry was heated at 70 ° C for 0.5 h and then cooled to 8 ° C. Water (100 mL) and ice (100 g) were added and the precipitated solid was filtered off, washed with water and dried in vacuo. This gave 6.3 g of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine.

187-191 ° C ¹ H NMR (CDCl ₃ ) δ 3.36 (t, 2H, J = 9 Hz); 3.45 (t, 2H, J = 9Hz); 7.14 (d, 1H, J = 9Hz); 7.50 (t, 1H, J = 9 Hz); 7.59 (t, 1H, J = 9 Hz); 7.77 (d, 1H, J = 9Hz); 7.85 (d, 1H, J = 9Hz); 7.91 (brs, 1H); 8.0 (d, 1H, J = 9Hz).

3-Chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-blazepin

6.2 g (22 mmol) of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine are dissolved in 200 ml of glacial acetic acid and the solution is placed under a nitrogen atmosphere. Sodium acetate trihydrate (3.8 g, 28 mmol) was added. After 5 minutes, 0.6 grams (10%) palladium on carbon was added and the reaction mixture was hydrogenated at atmospheric pressure with 450 mL of hydrogen gas at room temperature. The reaction mixture was filtered through Celite and the solvent concentrated in vacuo. After re-evaporating the toluene solution (250 mL), the resulting residue was suspended in water (100 mL), the suspension was stirred for 5 minutes and the precipitated solid was collected by filtration and dried under vacuum. 1.7 g of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine were obtained.

···············································•

k

1 H NMR (CDCl ₃ ) δ 2.64 - 2.74 (m, 1H); 2.85-2.95 (m, 1H); 3.09 - 3.18 (m, 1H); 3.50 - 3.55 (m, 1H); 4.49 (dd, 1H); 7.15 (d, 1H, J = 9Hz); 7.50 (t, 1H, J = 9 Hz); 7 .GO G. ÍK. J = 9 Hz); 7.78 (d, 1H, J = 9Hz); 7.80 (brs, 1H); 7.87 (d, 1H, J = 9Hz): 0.04 (d, 1H, J = 9Hz).

G -. / 7ifÍo-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b1azepin

To a suspension of 0.55 g (8.4 mmol) of sodium azide and 17 mL of DMSO was added 1.6 g (6.7 mmol) of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H; , iGo2 Hbjazepine was added. The suspension was then heated at 80 ° C for 7 hours for 3 hours. The hot reaction mixture was poured onto 30 grams of ice, the precipitate was filtered off and 200 grams of column chromatography were carried out. After purification with heptane at the beginning of the process, then a 1: 1 by volume mixture of heptane and diethyl acetate was used as eluent. 1.1 (π mm) of 5-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine was prepared.

m.p .: 180-192 ° C

1 H NMR (CDCl ₃ ) δ 2.44-2.53 (m, 1H); 2.64-2.75 (m, 1H); 3.04 - 3.14 (m, 1H); 3.53 - 3.60 (m, 1H); 3.89 (dd, 1H); 3.89 (dd, 1H); 7.15 (d, 1H, J = 9Hz); 7.50 (t, 1H. J = 9 Hz); 7.60 (t, 1H, J = 9Hz); 7.78 (d, 1H, J = 9Hz); 7.83 (brs, 1H); 7.87 (d. 1K. J = 9 Hz); 8.04 (d, 1H, J = 9Hz).

N-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine

A solution of 1.0 g (4.0 mmol) of 3-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] in zinc and 20 ml of dry THF was dissolved in an ice bath. and placed under an atmosphere of nitrogen gas. A solution of 0.17 g (4.4 mmol) of rHirium borohydride in 20 ml of ethanol was added dropwise to about 10 r.c. and the reaction mixture was refluxed for 20 hours. The volumetric components were evaporated in vacuo and the residue was columned. ···:, ·· ··:. ·; ··.

·· · ·· «

The residue was purified by chromatography on 200 g of silica gel eluting with dichloromethane, eluting with a 9: 1 by volume mixture of ethanol in 25% aqueous ammonia (0% to 10% gradient). 0.3 g of 3-amino-4-oxo-2,3,4,5-tetrahydro-1 H-naphtho [2,1-bjazepine] were obtained.

¹ H NMR (CDCl ₃ ) δ 2.05 - 2.15 (m, 1H); 2.64-2.75 (m, 1H); 2.95 - 3.05 (m, 1H); 3.44 (dd, 1H); 3.48 - 3.52 (m, 1H); 7.13 (d, 1H, J = 9Hz); 7.49 (t, 1H, J = 9Hz); 7.56 (t, 1H, J = 9Hz); 7.60 (d, 1H, J = 9Hz); 7.75 (d, 1H, J = 9Hz); 7.85 (d, 1H,

J = 9 Hz); 8.07 (d, 1H, J = 9Hz).

(1,1-Dimethyl-2- (4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) -ethyl) -carbamic acid tert-butyl ester

To a solution of 0.26 g (1.2 mmol) of 3-tert-butyloxycarbonylamino-3-methyl-butanoic acid and 15 ml of DMF was added 0.24 g (1.2 mmol) of EDAC. After 15 minutes at room temperature, 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine (0.25 g, 1.1 mmol) was added and the reaction mixture was stirred for 6 hours. Water (80 mL) was added and the solution was extracted with ethyl acetate (30 mL).

The organic layer was washed with sodium bicarbonate solution (20 mL) and water (20 mL) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on 50 g silica gel using heptane / ethyl acetate 1: 3 (v / v) as the eluent. In this way, 0.49 grams of (1,1-dimethyl-2- (4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-biazepin-3-ylcarbamoyl) ethyl) is obtained as a result ) -carbamic acid tert-butyl ester was prepared.

·· ···· ··· · · · · · · · · · ·

ΊΟ (1,1-Dimethyl-2- (4-oxo-5- (2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-ylmethyl) -2,3,4), 5-Tetrahydro-1H-naphtho [2,1-benzazin-3-ylcarbamoyl) -ethyl] -carbamic acid tert-butyl ester

0.23 grams (4.0 mmol) of dry powdered potassium hydroxide and 0.49 grams (1.0 mmol) of 1,1-dimethyl-2- (4-oxo-2,3,4,5-tetrahydro-1 H-naphtho [2.1 A solution of -b] azepin-3-ylcarbamoyl) -ethyl) -carbamic acid in tert-butyl ester and 15 mL of DMSO was stirred for 0.5 h under a nitrogen atmosphere. Then 0.59 g (1.1 mmol) of 5- (4'-bromomethyl-biphenyl-2-yl) -N- (triphenylmethyl) -tetrazole was added and the reaction mixture was stirred for 1 hour. 30 ml of 10% aqueous ammonium chloride solution, 100 ml of water and 60 ml of ethyl acetate were added and the separate phases were separated. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography over 100 grams of silica gel using heptane / ethyl acetate 2: 3 (v / v) as the eluent. In this way, 0.45 grams of (1,1-dimethyl-2- (4-oxo- (2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-ylmethyl) -methyl) -2,3,4) 5-Tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) -ethyl} -carbamic acid tert-butyl ester was prepared.

¹ H NMR (CDCl ₃ ) δ 1.26 (s, 2H); 1.34 (s, 6H); 1.42 (s, 9H); 2.46 (dd, 2H); 3.16 (dd, 1H); 4.45 (m, 1H); 4.74 (d, 1H); 5.26 (s, 1H); 5.31 (s, 1H); 6.70 (d, 1H); 6.93 (d, 1H); 7.00 (s, 4H); 7.21 - 7.35 (m, 8H); 7.39 - 7.53 (m, 5H); 7.71 (d, 1H); 7.80 - 7.92 (m, 3H).

0.45 g (0.67 mmol) of (1,1-dimethyl-2- (4-oxo- (2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-ylmethyl)) -2,3,4 , 5-Tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) · · ·

Ethyl) -carbamic acid tert-butyl ester was dissolved in 20 mL of dichloromethane and 2 mL of trifluoroacetic acid was added. After stirring for 4.5 hours, water (5 mL) was added. The solvent was evaporated in vacuo and the residue was purified by column chromatography over 40 g silica gel (Waters RP18 75 m) using methanol / water / TFA 60: 40: 0.5 (v / v) as the eluent. The solvent was evaporated in vacuo and the residue redissolved in methanol (30 mL) and the solution evaporated in vacuo. As a result, 0.31 g of the title compound was obtained.

¹ H NMR (d ₆ -DMSO) δ 1.19 (s, 3H); 1.25 (s, 3H); 2.13-2.46 (m, 3H); 2.40 (s, 1H); 2.41 (s, 1H); 3.40 (dd, 1H); 4.20 - 4.28 (m, 1H); 4.90 (d, 1H); 5.33 (d, 1H); 6.98 (d, 2H); 7.16 (d, 2H); 7.47 - 7.67 (m, 8H); 7.75 (brs, 2H); 7.89 - 7.98 (m, 2H); 8.14 (d, 1H); 8.69 (d, 1H).

HPLC: _Rt = 05.30 min (method "A" operating mode)

Analysis:

Calculated for C ₃₃ H ₃₃ N ₆ O ₂ , 11/2 TFA, 11/2 H ₂ O:

C, 57.23%; H, 4.99%; N, 12.98%.

Found: C, 57.35%; H, 4.81%; N, 12.60%.

Example 2

3-Amino-3-methyl-N- (4-oxo-5- (4- (4- (5-methyl-f1,3,41oxadiazol-2-yl) thien-3-yl) benzyl) -2 , 3,4,5-Tetrahydro-1H-naphtho [2,1-benzazepin-3-yl) butyramide

3,3-Dichloro-4-oxo-2,3,4,5-tetrahydro-1 H-naftof2,1 b1azepin

A suspension of 24.1 grams (114 mmol) of 4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine and 750 ml of toluene was prepared as described in Example 1 above. procedure. To the solution was added phosphorus pentachloride (71.3 grams, 342 mmol). The reaction mixture was slowly warmed to 90 ° C and maintained at this temperature for one hour. Activated carbon was added and the mixture was allowed to cool slowly to ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The oily residue was dissolved in 300 ml of glacial acetic acid, heated at 70 ° C for 30 minutes, and then cooled to 10 ° C. Water (1200 ml) was added and stirred in an ice bath for 15 minutes. The precipitated solid was collected by filtration, washed with water and dried in vacuo. This gave 28.3 grams of solid 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine.

¹ H NMR (CDCl ₃ ) δ 3.36 (dt, 2H); 3.45 (dt, 2H); 7.15 (d, 1H); 7.48 (t, 1H); 7.58 (t, 1H); 7.58 (t, 1H); 7.75 (d, 1H); 7.86 (d, 1H); 8.00 (d, 1H); 8.08 (brs, 1H). 3-Chloro-4-oxo-2,3,4,5-tetrahydro-1 H-naftof2,1 b1azepin

28.0 grams (100 mmol) of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho (2,1-bjazepine) were dissolved in glacial acetic acid (250 mL) and placed under nitrogen. To the solution was added 22.6 grams (275 mmol) of sodium acetate, 24.6 grams (280 mmol) of sodium hypophosphite hydrate and 1.5 grams of palladium on carbon (10% by weight) and the reaction mixture was stirred at 56 ° C under nitrogen for 20 hours. The mixture was allowed to cool to ambient temperature and filtered to give a solid which was boiled with THF (3 x 700 mL) and filtered while still hot, and the combined THF phases were evaporated in vacuo to give 19.1 g of 3-chloro-4. Oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine was obtained.

¹ H NMR (CDCl ₃ ) δ 2.65-2.73 (m, 1H); 2.85-2.95 (m, 1H); 3.11-3.19 (m, 1H); 3.50-3.56 (m, 1H); 4.49 (dd, 1H); 7.18 (d, 1H); 7.50 (t, 1H); 7.60 (t, 1H); 7.78 (d, 1H); 7.60 (t, 1H); 7.78 (d, 1H); 7.88 (d, 1H); 8.01 (brs, 1H); 8.04 (d, 1H).

3-Azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho-2,1-blazepine

For a suspension of 16.6 g (67.6 mmol) of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-bjazepine] and 80 ml of DMSO, 8.8 g (135 mmol) of sodium azide are added. and the suspension was heated at 60 ° C for 5 hours. The hot reaction mixture was poured into 1 liter of water. The precipitate was collected by filtration and washed with water. It was dried in vacuo to give 16.3 grams of 3-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine.

¹ H NMR (CDCl 3) δ 2.44 - 2.53 (m, 1H); 2.62-2.75 (m, 1H); 3.06 - 3.13 (m, 1H); 3.58 (dd, 1H); 3.90 (dd, 1H); 7.18 (d, 1H); 7.52 (t, 1H); 7.60 (t, 1H); 7.80 (d, 1H); 7.87 (d, 1H); 8.00 (brs, 1H); 8.06 (d, 1H).

3-Amino-4-oxo-2,3,4,5-tetrahydro-1 H-blazepin naftof2,1

3-Azido-4xo-2,3,4,5-tetrahydro-1 H-naphtho [2,1-b] azepine (16.0 g, 63.4 mmol) was dissolved in a mixture of dry dioxane (150 mL) and ethanol (150 mL) and treated with %) palladium was added. This mixture was hydrogenated at 5 x 10 ^{5 with} vigorous stirring for 24 hours. The reaction mixture was filtered and excess hydrogen chloride in ethanol was added. The precipitated solid was separated, washed with ethanol and dried to give 14.4 grams of 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine hydrochloride. 14.2 grams of the above hydrochloride were dissolved in 800 ml of water with heating and 25% by weight aqueous ammonia was added and a precipitate formed. The solid product was isolated by filtration, washed with water and concentrated in vacuo. 11.9 g of 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine were obtained.

¹ H NMR (CDCl ₃ ) δ 2.05-2.15 (m, 1H); 2.65-2.75 (m, 1H); 2.95-3.05 (m, 1H); 3.45 (dd, 1H); 3.5 (dd, 1H); 7.15 (d, 1H); 7.50 (t, 1H); 7.58 (t, 1H); 7.75 (d, 1H); 7.79 (brs, 1H); 7.86 (d, 1H); 8.08 (d, 1H).

4.5 g of 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine were dissolved in 250 ml of hot ethanol and then 50 ml of hot ethanol dissolved in L (+) - tartaric acid. to the solution at a temperature of 70 ° C. The resulting suspension was allowed to cool to ambient temperature with constant stirring. The solid was collected by filtration and washed with ethanol. It was then dissolved in 250 ml of boiling water, treated with activated charcoal and filtered hot. The filtrate was allowed to cool to ambient temperature with constant stirring and then stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to give 3.3 g of product, which was then dissolved in 200 ml of hot water. An excess of 25% aqueous ammonia was added at 40-50 ° C and the solid separated by filtration. After drying, 2.1 grams of unresolved 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine were obtained.

(1,1-Dimethyl-2- (4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-bazazin-3-ylcarbamoyl) -ethyl) -carbamic acid tert-butyl ester

3-tert-Butyloxycarbonylamino-3-methylbutanoic acid (2.43 g, 11.2 mmol) and 1-hydroxybenzotriazole (1.52 g, 11.3 mmol) were dissolved in DMF (30 mL) and placed under a nitrogen atmosphere. To the solution was added 2.19 g (11.4 mmol) of EDAC and the reaction mixture was stirred for 10 minutes at room temperature. Unsolvated 3-amino-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepine (2.3 g, 10.2 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water (200 mL) and the solution was extracted with dichloromethane (2 x 250 mL). The combined organic extracts were washed with 10% sodium bicarbonate (2 x 150 mL) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulting solid residue was suspended in diethyl ether. 4.5 grams (1,1-dimethyl-2- (4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) ethyl) by filtration and drying tert-butyl ester of carbamic acid was prepared.

¹ H NMR (CDCl ₃ ) δ 1.35 (s, 6H); 1.43 (s, 9H); 2.05 - 2.13 (m, 1H); 2.45-2.60 (m, 2H); 2.90 - 3.08 (m, 2H); 3.50 (dd, 1H); 4.50 - 4.56 (m, 1H); 5.22 (brs, 1H); 6.75 (d, 1H); 7.12 (d, 1H); 7.49 (t, 1H); 7.57 (t, 1H); 7.73 (d, 1H); 7.85 (d, 1H); 7.88 (brs, 1H); 8.03 (d, 1H).

A mixture of 3.3 g (13.2 mmol) of 5- (4- (4-methylphenyl) -3-thienyl) -tetrazole and 50 ml of acetic anhydride was heated under reflux for 1 hour. The resulting solution was concentrated in vacuo to give an oily residue which was then dissolved in 100 mL of ethyl acetate. The organic solution was washed with sodium bicarbonate (100 mL), treated with charcoal and dried over magnesium sulfate. It was filtered off and concentrated in vacuo. This gave 3.4 g of 5-methyl-2- (4- (4-methylphenyl) -3-thienyl) - [1,3,4] oxadiazole as an oil.

¹ H NMR (CDCl 3) δ 2.38 (s, 3H); 2.45 (s, 3H); 7.18 (d, 2H); 7.25 (d, 2H); 7.29 (d, 1H); 7.29 (d, 1H); 8.03 (d, 1H).

5-Methyl-2- (4- (4-bromo-phenyl) -3-thienyl f1,3,41oxadiazol

5-Methyl-2- (4- (4-bromomethylphenyl) -3-thienyl) - [1,3,4] oxadiazole (3.4 g, 13.3 mmol) was dissolved in carbon tetrachloride (60 mL). To the solution were added 0.21 g of AIBN, 0.52 g of sodium acetate, 2.6 g (14.6 mmol) of NBS and 0.52 ml of glacial acetic acid. The resulting reaction mixture was refluxed for 8 hours and then allowed to cool to ambient temperature. The reaction mixture was filtered through silica gel and the filtrate was concentrated in vacuo. The oily residue was dried in vacuo over sodium hydroxide. This gave 2.6 g of crude 5-methyl-2- (4- (4-bromomethylphenyl) -3-thienyl- [1,3,4] oxadiazole).

¹ H NMR (CDCl ₃ ) δ 2.47 (s, 3H); 4.55 (s, 2H); 7.32 - 7.35 (m, 3H); 7.40 (d, 2H); 8.08 (d, 1H).

(1,1-Dimethyl-2- (4-oxo- (4- (4- (5-methyl-f1,3,41oxadiazol-2-yl) -3-thienyl) benzyl) -2,3,4, 5-Tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl] -ethyl) -carbamic acid tert-butyl ester

2.0 g (29.8 mmol) of dry powdered potassium hydroxide and 3.2 g (7.46 mmol) of (1,1-dimethyl-2- (4-oxo-2,3,4,5-tetrahydro-1 H-naphtho [2,1-b]) A solution of azepin-3-ylcarbamoyl) -ethyl) -carbamic acid in tert-butyl ester and 30 ml of DMSO was stirred for 30 minutes under a nitrogen atmosphere. Then, 2.5 g (7.46 mmol) of 5-methyl-2- (4- (4-bromomethylphenyl) -3-thienyl) - [1,3,4] oxadiazole in DMSO (10 ml) was added and the reaction mixture was stirred for 1 hour. and stirred at ambient temperature. The mixture was poured into water (500 mL) and extracted with dichloromethane (600 mL). The organic extract was washed with water (100 mL), 5% tartaric acid (200 mL) and brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography over 200 g of silica gel using ethyl acetate as the eluent. In this way, 2.1 grams of (1,1-dimethyl-2- (4-oxo- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) -3-thienyl) benzyl) benzyl) benzyl is obtained as a result of the procedure. ) -2,3,4,5-Tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) -ethyl) -carbamic acid tert-butyl ester was obtained.

¹ H NMR (CDCl ₃ ) δ 1.33 (s, 6H); 1.40 (s, 9H); 1.48-2.05 (m, 1H); 2.28 (s, 3H); 2.42 (d, 1H); 2.54 (d, 1H); 2.60-2.70 (m, 1H); 2.75-2.85 (m, 1H); 3.29 (dd, 1H); 4.46-4.54 (m, 1H); 4.48 (d, 1H); 5.30 (brs, 1H); 5.50 (d, 1H); 6.72 (brs, 1H); 7.20-7.26 (m, 5H); 7.40 (d, 1H); 7.48-7.56 (m, 2H); 7.80 (d, 1H); 7.86 (d, 1H); 7.98 (d, 1H); 8.01 (d, 1H).

2.1 grams (3.43 mmol) of (1,1-dimethyl-2- (4-oxo- (4- (4- (5-methyl- (1,3,4) oxadiazol-2-yl) -3-thienyl) benzyl) benzyl) benzyl ) -2,3,4,5-Tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) -ethyl) -carbamic acid tert-butyl ester was dissolved in 100 mL of dichloromethane and 10 mL of Trifluoroacetic acid was added, the reaction mixture was stirred at ambient temperature for 3 hours, 100 mL of 1N sodium hydroxide solution was added and the separated phases were separated, the organic phase was treated with activated carbon and dried over magnesium sulfate. grams of the title compound were obtained.

¹ H NMR (CDCl 3) δ 1.22 (s, 3H); 1.25 (s, 3H); 2.10 - 2.18 (m, 1H); 2.26 (d, 1H); 2.29 (s, 3H); 2.32 (d, 1H); 2.60-2.75 (m, 5H); 3.27 - 3.33 (m, 1H); 4.53 - 4.60 (m, 1H); 4.90 (d, 1H); 5.47 (d, 1H); 7.20 - 7.25 (m, 5H); 7.43 (d, 1H); 7.49 - 7.56 (m, 2H); 7.79 (d, 1H); 7.85 (d, 1H); 7.98 (d, 1H); 8.00 (d, 1H); 8.40 (d, 1H).

HPLC: _Rt = 08.22 min ( "C" Procedure Mode) • ·

Analysis:

Calculated for C ₃₃ H ₃₃ N ₅ O ₃ S, 11/2 H ₂ O:

C, 65.3%; H, 6.0%; N, 11.5%.

Found: C, 65.2%; H, 6.0%; N, 10.9%.

Example 3

3- (2R) -Hidroxipropilamino) -3-methyl-N- (5- (4- (4- (5-methyl- [1,3.41oxadiazol-2-yl) thien-3-yl) benzyl) - 4-oxo-2,3,4,5-tetrahydro-1H-1-b1azepin naftof2 _l-3-yl) butyramide

(2R) -tetrahydropyran-2-yloxypropionaldehyde (107 mg, 0.675 mmol) was dissolved in methanol (10 mL) and 3-amino-3-methyl- (261 mg, 0.45 mmol) dissolved in a mixture of methanol (10 mL) and glacial acetic acid (0.1 mL). N- (5- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) thien-3-yl) benzyl) -4-oxo-2,3,4,5 -tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) -butyramide was added. To the mixture was added 57 mg (0.9 mmol) of sodium cyanoborohydride in 3 ml of DMF, and the reaction mixture was stirred at room temperature for 3.5 hours. The solvent was removed in vacuo and the residue was dissolved in a mixture of ethyl acetate (10 mL) and water (10 mL). The phases were separated and the organic phase was dried over magnesium sulfate and the solvent removed in vacuo. The residue was dissolved in 10 ml of methanol and 1 ml of a 3M solution of hydrogen chloride in ethyl acetate (3 mmol of HCl) was added. The mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo. The residue was dissolved in dichloromethane (10 mL) and washed with 1N sodium hydroxide solution (2 x 10 mL). The combined aqueous layers were extracted with dichloromethane (2 x 10 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was evaporated in vacuo. The crude product was isolated by flash chromatography on 100 mL silica gel using dichloromethane-ethanol-25% w / w aqueous ammonia (85: 15: 1) as eluent. As a result, 8 mg of 3 - ((2R) -hydroxypropylamino) -3-methyl-N- (5- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) thiene) A diastereoisomeric mixture of -3-yl) benzyl) -4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-biazepin-3-yl] butyramide was obtained.

¹ H NMR (CDCl ₃ ) δ 1.10-1.40 (m, 9H); 2.15-2.40 (m, 5H); 2.55-2.75 (m, 4H); 3.40 (m, 1H); 3.35 (m, 1H); 4.10 (m, 1H); 4.50 (m, 1H); 4.35 and 4.45 (both d, 1H together); 5.40 and 5.50 (both d, together 1H); 7.15 - 7.35 (m, 5H); 7.40 (m, 1H); 7.45 - 7.60 (m, 2H); 7.80 (dd, 1H); 7.85 (d, 1H); 7.95 (dd, 1H); 8.05 (d, 1H); 9.10 (m, 1H).

HPLC: _Rt = 27.8 min (B operating mode)

Example 4

1-Amino-cyclopropanecarboxylic acid ^(4-oxo-5-f2 - (1H-tetrazol-5-yl) biphenyl-4-ylmethyl-2,3,4,5-tetrahydro-1H-naftoí2, 1-Biazepin-3-yl) -amide (1- (4-Oxo-2,3,4,5-tetrahydro-1H-naphtho-2,1-biazepin-3-ylcarbamoyl) -cyclopropyl) -carbamic acid tert- butyl ester mg (0.37 mmol) of 1- (tert-butyloxycarbonylamino) cyclopropanecarboxylic acid was dissolved in 6 mL of DMF, followed by 50 mg (0.37 mmol) of HOAt and 71 mg (0.37 mmol) of EDAC. we added it. The reaction mixture was stirred for 10 min, then 84 mg (0.37 mmol) of 3-amino-4-oxo-3-amino-2,3,4,5-tetrahydro-1H-naphtho [2,1-bjazepine] and 96 mg (0.74 mmol) diisopropylethylamine was added and the mixture was allowed to stand at 40 ° C overnight. Water (60 mL) and ethyl acetate (60 mL) were added. The separated phases were separated and the organic phase was treated with 60 ml of 1 M hydrochloric acid solution and 60 ml of saturated sodium

washed with bicarbonate solution and dried over magnesium sulfate. The solvent was removed in vacuo to give 148 mg of crude solid. The product was recrystallized from a mixture of methylene chloride and ethyl acetate. As a result, 62 mg of (1- (4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-ylcarbamoyl) -cyclopropyl) -carbamic acid tert-butyl ester was obtained. we got.

¹ H NMR (CDCl ₃ ) δ 0.99 (s, 2H); 1.45 (m, 2H); 1.51 (s, 9H); 2.12 (m, 1H); 3.05 (m, 2H); 3.48 (m, 1H); 4.49 (m, 1H); 5.10 (brs, 1H); 7.05 - 8.05 (m, 8H). (1- (4-Oxo-5- (2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro-1H) Naphtho [2,1-benzazepin-3-ylcarbamoyl) -cyclopropyl] -carbamic acid tert-butyl ester mg (0.62 mmol) (1- (4-oxo-2,3,4,5-tetrahydro-1H-naphtho [ 2,1-b] Azepin-3-ylcarbamoyl) -cyclopropyl) -carbamic acid tert-butyl ester, together with dry powdered potassium hydroxide (34 mg, 0.62 mmol), was suspended in dry DMSO (2 mL) and stirred under nitrogen for 10 min. 5- (4'-Bromomethyl-biphenyl-2-yl) -N-triphenylmethyl-tetrazole (92 mg, 0.65 mmol) was added and the mixture was stirred for an additional 30 min, water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was dried over magnesium sulfate and evaporated to a residue of 1 ml, which was chromatographed on preparative Merck Silica plates using heptane-ethyl acetate 1: 1 (4: 1) as the eluent. She xo- (5- (2 '- (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro-1H-naphtho [2,1] -b] azepin-3-ylcarbamoyl) -cyclopropyl) -carbamic acid tert-butyl ester was obtained. ¹ H NMR (CDCl 3) δ 0.99 (s (br), 2H); 1.49 (s, 9H); 1.66 (s (br), 2H); 1.99 (m, 1H); 2.62 (m, 2H); 3.20 (m, 1H); 4.48 (m, 1H); 4.80 (d, 1H, J = 14 Hz); 5.09 (s (br), 1H); 5.25 (d, 1H, J = 14 Hz); 6.87 - 7.90 (m, 29 H).

EJ mg of (1- (4-oxo- (5- (2 ^'- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro- A mixture of 1 H-naphtho [2,1-b] azepin-3-ylcarbamoyl) -cyclopropyl) -carbamic acid tert-butyl ester and 1 ml of TFA was stirred under nitrogen for 2 hours, to which was added 1 drop of water and the solvent was removed under vacuum The residue was treated with 0.1 mL of methanol and 2 mL of diethyl ether, filtered and washed with 2 x 1 mL of diethyl ether to give 16 mg of 1-aminocyclopropanecarboxylic acid (4-oxo- (5- ( 2 '- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl) -2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) - amide trifluoroacetate was obtained.

¹ H NMR (CDCl ₃ OD) δ 1.30 (s, 2H); 1.65 (m, 1H); 2.15 (s, 2H); 3.38 (m, 2H); 3.45 (m, 1H); 4.35 (m, 1H); 4.92 (d, 1H, J = 15 Hz); 5.35 (d, 1H, J = 15 Hz); 6.98 - 8.15 (m, 14H).

HPLC: _Rt = 04.31 min (method "A" operating mode)

Example 5

3-Amino-3-methyl-N- (5-benzyl-4-oxo-2,3,4,5-tetrahydro-1 H-naphtho-2,1-blazepin-3-yl) -butyramide hydrochloride (1,1-dimethyl) -2- (4-Oxo-5-benzyl-2,3,4,5-tetrahydro-1H-naphtho-2,1-blazepin-3-ylcarbamoyl) -ethyl) -carbamic acid tert-butyl ester

250 mg (0.586 mmol) of (1,1-dimethyl-2- (4-oxo-5-benzyl-2,3,4,5-tetrahydro-1H-naphtho [2,1- b) Azepin-3-ylcarbamoyl) ethyl) -carbamic acid tert-butyl ester was dissolved in 5 mL DMSO and 131 mg (2.34 mmol) dry powdered potassium hydroxide was added. The reaction mixture was then stirred for 30 minutes under a nitrogen atmosphere. 105 mg (0.62 mmol) of benzyl34

bromide was added and the mixture was stirred for 75 minutes. Water (25 mL) and ethyl acetate (25 mL) were added and the separated layers were separated. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. This crude product was chromatographed on 60 Merck Silica plates using 2: 1 ethyl acetate / heptane as eluent. As a result, 142 mg of (1,1-dimethyl-2- (4-oxo-5-benzyl-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) carbamoyl-ethyl) -carbamic acid tert-butyl ester was obtained.

¹ H NMR (CDCl ₃ ) δ 1.34 (s, 6H); 1.40 (s, 9H); 1.99 (m, 1H); 2.55 (m, 1H); 2.75 (m, 1H); 3.25 (dd, 1H); 4.47 (m, 1H); 4.83 (d, 1H, J = 17 Hz); 5.30 (brs, 1H); 5.45 (d, 1H, J = 17 Hz); 6.71 (d, 1H, J = 10 Hz); 7.21 (s, 5H); 7.25 - 7.98 (m, 6H).

133 mg (0.26 mmol) of (1,1-dimethyl-2- (4-oxo-5-benzyl-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) Carbamoyl-ethyl) -carbamic acid tert-butyl ester was dissolved in 1.5 ml of 3 M ethyl acetate in hydrochloric acid and the solution was stirred overnight. Diethyl ether (5 mL) was added and the precipitated solid was filtered and washed with diethyl ether (2 x 1 mL). This gave 3-amino-3-methyl-N- (5-benzyl-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) -butyramide hydrochloride.

· · ··· · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · concerning on about about 200% on: ¹ H NMR (d ₆ -DMSO) δ 1.20 (s, 3H); 1.25 (s, 3H); 2.50-1.15 (m, 3H); 3.40 (m, 1H); 4.25 (m, 1H); 4.85 (d, 1H, J = 17 Hz); 5.45 (d, 1H, J = 17 Hz); 7.15-7.25 (m, 6H); 7.50-7.25 (m, 6H); 7.50-7.97 (m, 4H); 8.10 (d, 1H); 8.72 (d, 1H).

HPLC: R _t = 32.7 min (Method A)

Analysis:

C26H29N Calculated value to ₃ O _2, HCl, 2.11 H ₂ O:

C, 65.19%; H, 6.98%; N, 8.77%.

Found: C, 64.97%; H, 6.80%; N, 8.55%.

Claims (18)

Claims A compound of formula (I) wherein: R ¹ , R ² and R ³ are each independently hydrogen, halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylthio; n is 0 or 1; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and w is 0, 1, or 2; And X is -O-,> S (O) _m , or> NR ⁴ where R ⁴ is hydrogen or C 1-6 alkyl; m is 0, 1 or 2; A group is a or b, or c or d, each of which has one or two substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy. it may be substituted by alkylthio; and Y is = Ν-, Z is -O-, -S- or> NR ⁵ wherein R ⁵ is hydrogen or C 1-6 alkyl; Group B is selected from the group consisting of e or f or g or h, each of which has one or two substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy. it may be substituted by alkylthio; and Y and Z have the same meanings as defined above; M is -COOR ¹² , -CON R ¹² R ¹³ , -NHCONR ¹² R ¹³ or -SONR ¹² R ¹³ , wherein R ¹² and R ¹³ are each independently hydrogen, C 1-6 alkyl or C 4-8 cycloalkyl or M is one of the following isomers of tetrazole, triazole, oxadiazole, and thiadiazole, which is one of the following: · · · · · · · · · · · · · · · · · · · · · · · · they may be substituted with one or two substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylthio; D is a group of the formula wherein r and s are independently 0, 1, 2 or 3; Is ^R7 and ^R8 are independently hydrogen or C1-10 alkyl; or the R ⁷ and R ⁸ groups may be linked to form an alkyl bridge, the bridge being 2 to 6 carbon atoms; or each of R ⁷ and R ⁸ independently of one another can form an alkyl bridge (s) to one or all of R ⁹ or R ¹⁰ wherein the bridge consists of 2 to 5 carbon atoms; R ⁹ and R ¹⁰ are independently hydrogen, phenyl, substituted phenyl, branched or unbranched C 1 -C 10 alkyl, or branched or unbranched C 1 -C 10 hydroxyalkyl; or pharmaceutically acceptable salts thereof. The compound of claim 1, wherein the compound of formula (I) R ¹ , R ² and R ³ are each independently hydrogen, halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylthio; n is 0 or 1; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and w is 0, 1, or 2; X is -O-,> S (O) _m , or> NR ⁴ where R ⁴ is hydrogen or C 1-6 alkyl; m is 0, 1 or 2; »·» »•« • • • · · · · · · A group is a or b, or c or d, each of which has one or two substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy. it may be substituted by alkylthio; and Y is = Ν-, Z is -O-, -S- or> NR ⁵ wherein R ⁵ is hydrogen or C 1-6 alkyl; B is e or f or g or h, each of which has one or two substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy. it may be substituted by alkylthio; and Y and Z have the same meanings as defined above; M is -COOR ¹² , -CON R ¹² R ¹³ , -NHCONR ¹² R ¹³ or -SONR ¹² R ¹³ , wherein R ¹² and R ¹³ are each independently hydrogen, C 1-6 alkyl or C 4-8 cycloalkyl or M is a tetrazole, triazole, oxadiazole and thiadiazole isomer selected from one or two of the following substituents, namely, halogen, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio ; D is a group of the formula I in which r and s are independently 0-3; Is ^R7 and ^R8 are independently hydrogen or C1-10 alkyl; or the R ⁷ and R ⁸ groups may be linked to form an alkyl bridge, where the bridge consists of 2 to 6 carbon atoms; or each of R ⁷ and R ⁸ may independently be linked to one or all of R ⁹ or R ¹⁰ to form an alkyl bridge (s) wherein the bridge consists of 2 to 5 carbon atoms; R ⁹ and R ¹⁰ are independently hydrogen, phenyl, substituted phenyl, branched or unbranched C 1 -C 10 alkyl, or branched or unbranched C 1 -C 10 hydroxyalkyl; or pharmaceutically acceptable salts thereof. 3. A compound according to any one of claims 1 and 2 wherein w is 1. Compound according to any one of claims 1 to 3, characterized in that R ¹ , R ² and R ³ are hydrogen. A compound according to any one of claims 1 to 4 wherein q is 1 and A is j. A compound according to any one of claims 1 to 5 wherein B is k or I. The compound of claim 6, wherein the oxadiazole is 1,3,4-oxadiazole. A compound according to any one of claims 1 to 7, wherein r is 1, s is 0, each of R ⁷ and R ⁸ is C 1 to C 6; each of R ⁹ and R ¹⁰ is hydrogen or one of R e and R ¹⁰ is C 2 hydroxyalkyl and the other is hydrogen. £. A compound according to claim 8, wherein R ⁷ and R ⁸ are each methyl. 1C. A compound selected from the group consisting of: - Smino-3-methyl-N- (4-oxo-5- (2 ^, - (tetrazol-5-yl) biphenyl-4-ylmethyl) -2,3; 4,5-Tetrahydro-1H-naphtho [2.1-b] azepin-3-yl) -butyramide, smino-3-methyl-N- (4-oxo-5- (4- (4- (5- methyl- [1,3,4] oxadiazol-2-yl) -thien-3-yl) -benzyl) -2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) butyramide, 3R, 1R, 1-hydroxypropylamino) -3-methyl-N- (5- (4- (4- (5-methyl- [1,3,4] oxadiazol-2-yl) thienyl) phenyl) -4- -oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) butyramide, isminocyclopropanecarboxylic acid (4-oxo-5- [2 '- ( 1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) -amide, 3-Smino-3-methyl-N- (5-benzyl-4-oxo-2,3,4,5-tetrahydro-1H-naphtho [2,1-b] azepin-3-yl) -buroamide. 11. A pharmaceutical composition comprising, as active ingredient, a pharmaceutically acceptable carrier or diluent, the compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof. · · · · · · · · · · · · · · · · · · · · 12. The pharmaceutical composition of claim 11, wherein the unit dosage form is about 0.0001 mg and about 500 mg 1-10. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition for stimulating pituitary growth hormone production, comprising, as active ingredient, a pharmaceutically acceptable carrier or diluent, the compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. An oral, transdermal, pulmonary, or parenteral administration of a pharmaceutical composition according to claim 12 or claim 13. 15. A method of stimulating pituitary growth hormone production, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 10. The method of claim 15, wherein the effective amount of a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, is from about 0.0001 mg / kg to about 100 mg / kg / day, preferably about 0.001 / day. mg / kg body weight to about 50 mg / kg body weight. ·· ··· ··· · ··· · · The use of a compound according to any one of claims 1 to 10, or pharmaceutically acceptable salts thereof, as a medicament. Use of a compound according to any one of claims 1 to 10, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for stimulating pituitary growth hormone production. 19. A process for the manufacture of a medicament for the treatment of disorders or diseases resulting from growth hormone deficiency, comprising combining an effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, with a suitable carrier and / or diluent. , nasal or dermal, by injection or infusion. 20. Any new feature or combination of described solutions.